Although macrophages and CD4+ T cells are the major targets for HIV infection, the susceptibilities to HIV infection are different in these two cell types and depend on the activation state of cells. Activated CD4+ T cells are more susceptible to HIV infection than quiescent T cells. Likewise, macrophages are more susceptible to productive HIV infection than freshly isolated monocytes. Supporting this observation, blood monocytes are rarely infected during acute or early infection, even though they express CD4 and chemokine receptors. However, the critical events which take place during cellular differentiation and which render tissue macrophages permissive to HIV remain obscure. A goal of this study is to identify these limiting factors in order to develop novel anti-viral therapies. Previous work explored the possibility that the expression of entry receptors, such CD4 and CCR5, represents a limiting factor for HIV replication in blood monocytes. However, the results obtained were not only inconclusive, but they also suggested that factors, other than entry receptors, control the threshold of permissivity of monocytes and macrophages. Thus, although macrophages have been recognized almost twenty years ago to be key players in HIV pathogenesis, the factors that render them permissive to HIV still remain to be identified. In this study, we propose to identify the events, which occur during the differentiation of blood monocytes into tissue macrophages that lead to the susceptibility to HIV infection. Specifically, we propose to examine the role of the surrounding extracellular matrix (ECM) and the contribution of a novel class of macrophages receptors, the syndecans, to the susceptibility of macrophages to HIV.